Back to Search
Start Over
Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor.
- Source :
-
International journal of oncology [Int J Oncol] 2018 Oct; Vol. 53 (4), pp. 1681-1690. Date of Electronic Publication: 2018 Aug 01. - Publication Year :
- 2018
-
Abstract
- Adult T‑cell leukemia/lymphoma (ATLL) constitutes an aggressive malignancy caused by human T‑cell leukemia virus type 1 (HTLV‑1) that is resistant to available chemotherapeutics. The constitutive activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is an important feature of ATLL, and spleen tyrosine kinase (SYK) is overexpressed in HTLV‑1-transformed T‑cell lines. In this study, we evaluated the effects of SYK- (PRT060318) or JAK- (JAK inhibitor 1) selective inhibitors and the dual SYK/JAK inhibitor, cerdulatinib, on the viability of HTLV‑1-transformed and ATLL-derived T‑cell lines. Cell proliferation, viability, cell cycle, apoptosis and intracellular signaling cascades were analyzed by the water-soluble tetrazolium-8 assay, flow cytometry and western blot analysis. HTLV‑1-infected T‑cell lines were sensitive to both SYK-selective and pan-JAK inhibitors, whereas cerdulatinib more potently suppressed cell proliferation and reduced cell viability than either of these agents alone. By contrast, the cytotoxic effects of cerdulatinib on uninfected T‑cell lines and peripheral blood mononuclear cells from a healthy donor were less pronounced. Cerdulatinib induced cell cycle arrest in the G2/M phase, which was associated with a decreased cyclin-dependent kinase 1 and cyclin B1, and an increased p21 and p27 expression. Hoechst staining revealed chromatin condensation and nuclear fragmentation in the cells treated with cerdulatinib, and an increased fraction of apoptotic APO2.7-stained cells was detected by flow cytometry. This corresponded to the activation of caspase-8, -9 and -3, and decreased levels of the anti-apoptotic factors, Bcl-xL, survivin, X-linked inhibitor of apoptosis (XIAP) and c‑FLIP. The cerdulatinib-induced decrease in cell viability was partly reversed by the caspase inhibitor, z‑VAD‑FMK. These anti-ATLL effects were associated with the suppression of SYK and JAK/STAT signaling, along with that of the downstream factors, AKT, ERK, activator protein‑1 and nuclear factor-κB. Finally, oral dosing with cerdulatinib lowered the tumor burden in a murine model of ATLL. Thus, our findings indicate that the simultaneous inhibition of therapeutically relevant targets, such as SYK and JAK is a more effective approach than single-agent therapy for the treatment of ATLL.
- Subjects :
- Animals
Benzimidazoles pharmacology
Benzimidazoles therapeutic use
Cell Line
Cell Survival drug effects
Cyclohexylamines pharmacology
Cyclohexylamines therapeutic use
Drug Evaluation, Preclinical
Female
Human T-lymphotropic virus 1 pathogenicity
Humans
Leukemia-Lymphoma, Adult T-Cell virology
Mice, Inbred ICR
Mice, SCID
Protein Kinase Inhibitors therapeutic use
Pyridones pharmacology
Pyridones therapeutic use
Pyrimidines pharmacology
Pyrimidines therapeutic use
Signal Transduction drug effects
Sulfones pharmacology
Sulfones therapeutic use
T-Lymphocytes
Treatment Outcome
Xenograft Model Antitumor Assays
Janus Kinases antagonists & inhibitors
Leukemia-Lymphoma, Adult T-Cell drug therapy
Protein Kinase Inhibitors pharmacology
Pyrimidines pharmacokinetics
Sulfones pharmacokinetics
Syk Kinase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1791-2423
- Volume :
- 53
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of oncology
- Publication Type :
- Academic Journal
- Accession number :
- 30066853
- Full Text :
- https://doi.org/10.3892/ijo.2018.4513